There is emerging evidence for an endocrine function of bone that plays a key role in regulating phosphate homeostasis and vitamin D metabolism through the release of the hormone FGF23 by osteoblasts and osteocytes. Defining the molecular mechanisms controlling FGF23 production by bone is of critical importance in understanding the physiological and pathological role of this hormone. Studies elucidating the genetic basis for hereditary hypophosphatemic disorders and mutant mouse models have identified the endopeptidase Phex, the SIBLING protein Dmp1, and the endonuclease Enpp1, as local regulators of both the mineralization of extracellular matrix and Fgf23 production in bone. Activation of FGFR1/PI3K/Akt/?-catenin and HMW-FGF2-dependent integrative fibroblastic growth factor receptor signaling (INFS) appear to couple bone mineralization with FGF23 release as well as integrate the effects of systemic factors, such as the PTH receptor/GNAS pathway, which has context-dependent effects on FGF23 gene transcription in osteoblasts /osteocytes. In addition, 1,25(OH)2D functions as a counter-regulatory hormone for FGF23, directly regulates FGF23 gene transcription through VDR-mediated mechanisms and is required for PTH regulation of FGF23 expression. This project proposes to understand how FGF23, vitamin D, PTH, Phex, Dmp1, and FGFR1 are integrated into a biological network that permits cross talk between systemic factors, the extracellular matrix mineralization process and osteoblast/osteocyte production of FGF23 to coordinate systemic phosphate and vitamin D homeostasis and bone formation/ mineralization. We propose studies that investigate the convergence of these local bone and systemic factors through canonical FGFR1, INFS, PTH and VDR-dependent signaling pathways to control basal and stimulated transcription of FGF23 in osteoblasts and osteocytes. We also propose to assess the relative roles of canonical FGFR1 and INFS in regulating FGF23 gene transcription both in vitro using osteoblasts derived from Phex-deficient Hyp and Dmp1-/- mice and in vivo by the conditional deletion of FGFR1 from osteoblasts and osteocytes of Hyp and Dmp1-/- mice. In addition, we will investigate cross-talk between 1,25(OH)2D, PTH and FGFR1 pathways in regulating FGF23 gene transcription in osteoblasts in vitro. These studies will lead to new knowledge of a complex systems biology that has evolved to permit cross-talk between bone and kidney to coordinate phosphate balance, vitamin D metabolism and bone mineralization. Such knowledge will help us understand and better manage patients with hyperphosphatemic and hypophosphatemic disorders. PUBLIC HEALTH RELEVANCE: We have discovered that bone is an endocrine organ in which osteoblasts and osteocytes release FGF23, a phosphaturic hormone that participates in a bone-kidney axis to regulate phosphate, vitamin D and mineral homeostasis. We are pursuing studies to define the precise signaling pathways linking the mineralization of extracellular matrix with FGF23 production in bone, to establish that a physiological function of FGF23 is to coordinate bone mineralization and renal handling of phosphate, and to understand the complex interactions between PTH and 1,25(OH)2D and actions of local bone derived factors through FGFR1 to regulate FGF23 gene transcription. Overall our work is establishing a new conceptual framework whereby bone communicates with other organs to regulate phosphate and vitamin D metabolism in response to changing physiological requirements and is leading to a better understanding of the pathogenesis, diagnosis and treatment of hyperphosphatemic and hypophosphatemic disorders.